Psoriasis is a common, immunologically-mediated, inflammatory and hyperproliferative disease of the skin and joints, with a multifactorial genetic basis. We have mapped PSORS1, the major psoriasis susceptibility gene in the major histocompatibility complex (MHC), to within or very near HLA-Cw6 by DNA sequencing and recombinant ancestral haplotype mapping. We have also confirmed associations between psoriasis and the HLA-B46-Cw1 haplotype in Thais, demonstrating that PSORS1 manifests allelic heterogeneity. Furthermore, we collected evidence for additional genetic effects elsewhere in the MHC. In an effort to identify non-MHC psoriasis genes, we have assembled a collection of 2,409 cases and 2,272 controls of Caucasian origin at the University of Michigan, and used some of them to carry out a genome-wide Collaborative Association Study of Psoriasis (CASP) with support from the Genetic Association Information Network (GAIN). With collaborators from Washington University at St. Louis and the University of Utah, we typed 451,724 single nucleotide polymorphisms (SNPs) on 1,384 unrelated psoriasis cases and 1,414 controls. After initial follow-up genotyping of 20 SNPs showing strong evidence of association in the initial scan, we have confirmed evidence of association at seven loci. Of these loci, three confirm previous reports of association (at HLA-C, IL12B, IL23R) and four identify novel signals located near plausible candidate genes (IL23A, IL13, TNFAIP3, and TNIP1). Together, these results strongly support the hypothesis that immunoregulatory genes are associated with psoriasis, and suggest that many more psoriasis susceptibility genes remain to be identified. In pursuit of this hypothesis, we propose the following specific aims: 1. Expand our sample collection. We will collect blood samples, along with detailed and uniform phenotypic data, on 2,000 Indian cases and 2,000 Indian controls, as well as 1,000 additional Caucasian psoriasis cases and 1,000 Caucasian controls. 2. Execute a genome-wide association scan in non-Caucasian samples. We will carry out a genome- wide association scan of 1,000 Indian cases and 1,000 Indian controls, using the remaining 1,000 Indian cases and 1,000 Indian controls for sample for confirmation and follow-up. Our proposed two stage design should allow us to identify additional susceptibility loci in a cost effective manner. 3. Complete the identification of the PSORS1 gene(s) by recombinant ancestral haplotype analysis. This will be accomplished by utilizing the results of CASP and its follow-up studies, together with additional genotyping of existing subjects and those to be collected in Aim 1. This analysis will take advantage of a large collection of phased MHC genotypes and a novel bioinformatics algorithm that will allow us to identify common structural motifs on multiple HLA alleles. 4. Characterize confirmed psoriasis susceptibility loci outside the MHC. We will utilize our existing case- control and family samples to identify functional variants in regions of strong, confirmed association, and to explore their functional consequences. This will be accomplished by identifying known and novel polymorphisms in these regions and testing them for disease association. PUBLIC HEALTH RELEVANCE: Psoriasis is a common inflammatory disease of the skin and joints, affecting over 4 million Americans. Its cause is not well understood. Identification of genes that increase risk of psoriasis will help us unlock the secrets of this troubling disease, and identify targets for more specific and effective therapy.